ABSTRACT ? Overall Progress in aging research over the last two decades has now firmly established an important role for DNA damage and genome instability in age-related cellular degeneration and death. Since its inception in 1999 investigators in this PPG demonstrated that genetic defects in some but not all DNA repair pathways are associated with premature aging phenotypes in mice, developed the first methods to detect spontaneous DNA mutations in primary tissues, identified transcription stress as a novel age-related molecular phenotype, developed a mouse model to detect and eliminate senescent cells in mice and subsequently demonstrated causality in aging phenotypes, and provided the first evidence that rare genetic variants in genome maintenance pathways are enriched in human centenarians. Studies from other groups have confirmed many of our conclusions, and genome instability is now regarded a hallmark of aging. However, what remains lacking is specific insight into the genetic control and molecular mechanisms that link DNA damage and genome instability to aging and longevity in humans. This renewal application is organized around three major research questions that remain in this field: (1) the key genome maintenance genotypes that control human aging and longevity; (2) the genetic and molecular basis of DNA damage-driven aging; and (3) How DNA damage and its molecular sequelae affect cell fate diversity in aging. These key questions will be addressed jointly and in an integrated manner by four research projects, an Administrative Core and a Bioinformatics Core. We expect that the resulting specific insight into the role of DNA damage and repair in human aging will give us the means to develop interventions to minimize the adverse effects of DNA damage metabolism.